The principle synthetic target in this proposal is phorboxazole B, a remarkably potent anticancer agent. Phorboxazole B was tested against the NCI's panel tumor cell lines and was found, for example, to inhibit the growth of colon tumor cells HCT-116 (GI50 4.36 X 10(-10) M). Two of the key segments of phorboxazole were prepared in the previous grant period using our segment-coupling Prins cyclization. Completion of the synthesis will be accomplished by assembly of the macrolide A and attaching the side chain B . Synthetic phorboxazole will be made available to collaborators to evaluate its mode of action, and to evaluate its potential as an anticancer agent. We are developing Prins cyclizations for the synthesis of complex tetrahydropyran rings found in many natural products. In this new grant period we will investigate the stereoselectivity and regioselectivity of the segment-coupling Prins cyclization. A regioselective version of this reaction is the key step in a proposed synthesis of the natural product ratjadone. We will also develop two new oxacarbenium ion cyclizations: the Mukaiyama aldol-Prins (MAP) cyclization and the carbon-trapping Prins cyclizations. Simple versions of both of these new reactions have been demonstrated and presented in the progress report. The MAP reaction combines a Mukaiyama aldol reaction of alkyl enol ether with a Prins cyclization to produce two new carbon-carbon bonds, one new ring and several stereogenic centers. It is the basis for a proposed highly convergent synthesis of leucascandrolide A. The carbon-trapping Prins cyclization produces two new carbon-carbon bonds, one ring and several stereogenic centers. It is the basis of a proposed synthesis of epicalyxin F, an anticancer compound isolated from a traditional Chinese medicinal plant. These new methods will be powerful tools for the assembly of tetrahydropyran natural products. Each of the synthetic targets selected for investigation has antitumor activity. Phorboxazole B is clearly the most important because of its extreme potency and because of the dearth of naturally available material. However, the other synthetic targets, leucascandrolide A, epicalyxin F and ratjadone also have interesting antitumor activity, and these synthetic products will be made available to collaborators for evaluation.